In this R-01 granting period we have identified an apoptotic protein isolated from the CD141/low CD16/high 43/HIV human macrophage hybridoma cell line. The apoptotic protein corresponds to the human hypothetical protein FLJ21908 that we have renamed as the SHIVA (soluble HIV apoptotic) protein. SHIVA may contribute to the generalized state of apoptosis in HIV-1 infected patients and may also play a role in the neurological complications of AIDS especially HIV associated dementia (HAD) since it induces apoptosis in primary neurons and neuronal cell lines. SHIVA can be co-localized in brain macrophages of patients with HAD by immunohistochemistry and can be detected by ELISA and real time PCR in the cerebrospinal fluid of patients with HAD but not in HIV infected patients without dementia, or normal controls. We have identified a candidate receptor (MW 100 kDa) for SHIVA and have also demonstrated that SHIVA-induced apoptosis can be blocked by memantine in SH-SY5Y neuronal cells. SHIVA is induced four weeks after infection in the 43Hrv cells and causes apoptosis by activating Bad and Bax, suppressing Bcl and Bcl-xL, and releasing cytochrome c from the mitochondria that activates caspase 9 and caspase 3. Anti-oxidants and transfected Bcl-2 blocks SHIVA-induced apoptosis. In this second re-submission in response to the further recommendations of the Reviewers, we will again focus first on the natural history of SHIVA production in the 43HW cells in vitro investigating both viral and host cell factors involved in its regulation, second on the identification of a SHIVA receptor and third on its role in HIV associated dementia (HAD) correlating the presence of SHIVA with apoptosis in brain tissue of HIV patients with and without HAD.